Despite the passage of decades-long investigations by many different research investigators and clinical practitioners, many of the mechanisms involved in the development of cancers or neoplasms remain unknown or poorly understood at best. The accumulated knowledge to date, however, has made clear that successive and progressive genetic modifications in the cell and the attendant biochemical changes resulting therefrom play a major role in the development of tumors, particularly malignant cells and tissues. See for example: Lewin, B., Genes V. Oncogenes: Gene Expression and Cancer, Oxford University Press, 1994, pp. 1181-1229; Sager, R., Science (Washington, D.C.), 246: 1406-1412 (1989); Weinberg, R. A., Cancer (Phila.) 70: 1653-1658 (1992); Cotran et al., "Pathologic Basis of Disease," in Neoplasia, W.B. Saunders Co., 1994, pp. 241-303; Lee et al., J. Cell Biol. 118: 1213-1221 (1992); Lee et al., Proc. Natl. Acad. Sci USA 88: 2825-2829 (1991); and Chassin et al., Cancer Res. 54: 5217-5223 (1994).
Among the different genetic and biochemical changes associated with the progression of events constituting an ongoing neoplastic development in cells and tumors, at least two have sparked major interest and substantial enthusiasm among cancer research investigators recently. These are: The existence of PDZ domains within new proteins expressed intracellularly, and the isolation of a novel membrane associated protein, MAP17. Each of these will be summarily reviewed.
Proteins having PDZ Domains
The term "PDZ" historically corresponds to the initials of three unusual proteins, each of these proteins containing one or more specific interaction domains or regions as a functional part of their individual protein structures. These three proteins are: (a) mammalian post synaptic density protein, PSD-95 [Cho et al., Neuron 9: 929-942 (1992)]; (b) Drosophila disc large tumor suppressor protein [Woods, D. F. & P. J. Bryant, Cell 66: 451-464 (1991)]; and (c) the tight junction protein, Z0-1 [Willott et al., Proc. Natl. Acad. Sci. USA 90: 7834-7838 (1993)] . Since the original three PDZ domain-containing proteins were first identified and characterized, more than 50 other cytoplasmic proteins containing one or more PDZ interaction-domains have been located in areas of cell--cell contacts and synaptic junctions [Doyle et al., Cell 85: 1067-1076 (1996); Songyang et al., Science 275: 73-77 (1997)].
The PDZ domain containing proteins known to date vary greatly in range and diversity of biological/biochemical functions. Many of these PDZ domain cytoplasmic proteins are demonstrably involved in control of cell proliferation, in cell differentiation and tissue development, and in synaptic organization [Woods, D. F. & P. J. Bryant, Cell 6: 451-464 (1991); Cho et al., Neuron 9: 929-942 (1992); Li et al., Science 257: 1225-1230 (1992); Kim et al., Nature 378: 85-88 (1995); Weinman et al., J. Clin. Invest. 95: 2143-2149; and Poulat et al., J. Biol. Chem. 272: 7167-7172 (1997)].
The true function of the PDZ domains as such, however, is not yet completely understood. The PDZ domains found within the protein structure are involved in protein interactions within the cytoplasm of the cell, usually in the locale of cell--cell contacts; but such proteins are also found in the nucleus of the cell, where they play a role in tissue differentiation and development. The most recent data reported in the scientific literature suggests that proteins containing multiple PDZ domains allow the recruitment of particular molecules involved in signaling pathways within the cell and also help organize the assembly of such signaling molecules into large complexes at the membrane-cytoplasm interface [Tsunoda et al., Nature 388: 243-249 (1997); Yun et al., Proc. Natl. Acad. Sci. USA 94: 3010-3015 (1997)] . The novel expression and intracellular production of a new protein demonstrably having one or more PDZ domains is therefore presently believed to be major event associated with a progressive loss of cell regulatory control and normal cell function.
The Membrane Associated Protein, MAP17
The membrane associated protein, MAP17, was only recently identified in 1995; and within medically normal cells is significantly expressed only at the brush border of proximal tubular epithelial cells of the kidney [Kocher et al., Clin. Cancer Res. 1: 1209-1215 (1995)] . However, MAP17 is overexpressed in a high percentage of carcinomas derived from kidney, colon, breast, and lung; and is associated with the cell membrane either in an apical distribution pattern or in areas of cell--cell contacts [Kocher et al., Am. J. Pathol. 149: 493-500 (1996)] . Moreover, overexpression of MAP17 in a colon carcinoma cell line (transfected HT29 cells) produced a marked decrease (down regulation) in cell proliferation in-vitro and in tumor growth in-vivo. Consequently, it is presently believed that novel and newly expressed proteins which demonstrably interact with MAP17 are actively involved in the progression of events and changes associated with the development of neoplasms, particularly malignant tumors.
Clearly, the transformation of a medically normal cells and tissues into an abnormal condition, and then progressively into a neoplastic or cancerous state is a multistep process occurring over time. Despite the abundance of information and knowledge accumulated in the scientific literature describing and characterizing the malignant transformation process, few biochemical markers or indicators of the progressive loss of cellular regulatory controls and increasing cell dysfunction have been identified to date. For these reasons, were an accurate, reliable, and detectable biochemical marker to be isolated which is indicative of an ongoing neoplastic development and identifies a progressively-worsening abnormal state within particular cells and tissues, such a marker would be recognized as a major advance and long-sought achievement within this technical field.